A potentially powerful approach to unravelling autoimmune disease mechanisms is to study one of the few known monogenic disorders. Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy, or APECED, is an autoimmune polyglandular syndrome inherited in an autosomal recessive manner due to a single susceptibility gene. This gene encodes AIRE, a protein with demonstrated transactivation potential, and with several structural domains suggestive of a transcription factor, including PHD-type zinc-finger motifs and a SAND putative DNA-binding stretch. AIRE and its murine homologue, aire, have a very restricted pattern of expression, highly elevated in the minute UEA-1+ subset of thymic medullary epithelial cells and somewhat enriched in thymic and peripheral dendritic cells. This pattern is of considerable interest because these same medullary epithelial cells have recently been implicated in the ectopic thymic synthesis of "organ-specific" peripherally expressed proteins such as insulin and proteolipid protein, and are increasingly incriminated in the negative selection of thymocytes; in addition, dendritic cells appear to have a role in both central and peripheral tolerance. Therefore, we hypothesize that APECED patients develop systemic autoimmunity because AIRE plays some critical role in tolerance induction to peripherally expressed proteins. To evaluate this hypothesis we will: I. generate and characterize a strain of aire-deficient mice; II determine whether aire controls the expression of other genes and, if so, which ones; and III. isolate and characterize dendritic cells from aire-deficient patients. We anticipate that results from these studies will provide new insights into the mechanisms of tolerance induction and the development of autoimmunity.